Rosmarinic acid antagonizes activator protein-1-dependent activation of cyclooxygenase-2 expression in human cancer and nonmalignant cell lines.
One mechanism through which bioactive food components may exert anticancer effects is by reducing the expression of the proinflammatory gene cyclooxygenase-2 (COX-2), which has been regarded as a risk factor in tumor development. Rosmarinic acid (RA) is a phenolic derivative of caffeic acid present in rosemary (Rosmarinus officinalis). Previous research documented that RA may exert antiinflammatory effects. However, the mechanisms of action of RA on COX-2 expression have not been investigated. Here, we report that in colon cancer HT-29 cells, RA (5, 10, and 20 micromol/L) reduced the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 promoter activity (P < 0.05) and protein levels (P < 0.05). In addition, the cotreatment with RA reduced (5 micromol/L, P < 0.05; 10 and 20 micromol/L, P < 0.01) TPA-induced transcription from a control activator protein-1 (AP-1) promoter-luciferase construct and repressed binding of the AP-1 factors c-Jun (10 micromol/L; P < 0.01) and c-Fos (10 micromol/L; P < 0.05) to COX-2 promoter oligonucleotides harboring a cAMP-response element (CRE). The anti-AP1 effects of RA were also examined in a nonmalignant breast epithelial cell line (MCF10A) in which RA antagonized the stimulatory effects of TPA on COX-2 protein expression (5 micromol/L, P < 0.05; 10 and 20 micromol/L, P < 0.01), the recruitment of c-Jun and c-Fos (10 micromol/L; P < 0.01) to the COX-2/CRE oligonucleotides, and activation of the extracellular signal-regulated protein kinase-1/2 (ERK1/2) (10 micromol/L; P < 0.01), a member of the mitogen-activated protein kinase pathway. Additionally, RA antagonized ERK1/2 activation in colon HT-29 and breast MCF-7 cancer cells (10 micromol/L; P < 0.01). Thus, we propose that RA may be an effective preventative agent against COX-2 activation by AP-1-inducing agents in both cancer and nonmalignant mammary epithelial cells.
Scheckel
Kristen A
KA
Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85718, USA.
Degner
Stephanie C
SC
Romagnolo
Donato F
DF
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D053630:Depsides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000097123:Rosmarinic Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002934:Cinnamates; D051546:Cyclooxygenase 2; D053630:Depsides; D048049:Extracellular Signal-Regulated MAP Kinases; D018808:Transcription Factor AP-1; D000097123:Rosmarinic Acid